Monday, February 18, 2013

Silibinin: An old drug in the high tech era of liver transplantation

Silibinin: An old drug in the high tech era of liver transplantation

Journal of Hepatology
Volume 58, Issue 3 , Pages 409-411, March 2013

Article Outline

Keywords: silibinin, liver transplantation, hepatitis C
HCV re-infection after liver transplantation is constant and accelerated in patients who are PCR-positive at the time of transplantation. Reinfection significantly impairs patient and graft survival [1]. At present, there are limited options available to prevent graft reinfection after transplantation or to successfully treat reinfected patients. Pretransplant antiviral combination therapy with (peg)interferon/ribavirin (PegIFN/RBV) is poorly tolerated and not very effective in patients infected with HCV genotype 1. In a prospective randomized controlled study, pretransplant treatment with PegIFN/RBV prevented post-transplant recurrence of HCV in 22% of a highly selected group of patients with HCV genotypes 1,4,6 [2]. Treatment after transplantation has also a limited efficacy and is associated with serious adverse effects. Currently, studies using triple therapy with PegIFN/RBV and a protease inhibitor (boceprevir or telaprevir) are ongoing, but again poor tolerance is a major issue.
Thus there is urgent medical need to develop safe and effective treatments for this group of patients. Two case reports indicated that therapy with intravenous silibinin (iv-SIL; Legalon SIL®, Rottapharm–Madaus) successfully eradicated the virus after transplantation [3], [4]. Based on these encouraging observations, iv silibinin got EMA orphan drug designation for prevention of recurrent hepatitis C. Iv-SIL is a 1:1 mixture of silibinin A and silibinin B and is available as intravenous therapeutic agent for treatment of mushroom poisoning. However, acute liver failure related to mushroom (amanita or lepiota) poisoning is an uncommon condition and there is no definitive evidence that silibinin improves the outcome of these patients.

In 2008, the potent antiviral activity of iv-SIL against HCV was described [5] and confirmed by in vitro studies [6]. Silibinin inhibits the HCV NS5B polymerase activity directly [7] or by interfering with the binding of the RNA to this enzyme [8]. Furthermore, the mechanisms of the antiviral action of silibinin appear also to include blocking of virus entry, transmission, and secretion (for review see [9]).

In this issue of the Journal, 2 groups from Spain report their experience with iv-SIL in the transplant setting [10], [11]. Both studies involved only a very small number of patients, but both included a control group: in the study performed in Madrid this was a historical control [10], while in the one performed in Barcelona, patients in the control group were treated with a placebo according to a prospective randomized, double-blind, placebo-controlled design [11].The Madrid group [10] started iv-SIL during the anhepatic phase and continued treatment for 21days. In contrast, the Barcelona group [11] treated patients for up to 21days prior transplantation, and continued or restarted the infusion for further 7days after transplantation. Both studies confirmed the robust antiviral efficacy and the safety of iv silibinin in this difficult-to-treat patients, with the apparent lack of interaction with immunosuppressants, but not surprisingly, both approaches failed to eradicate the virus in a single patient, although quite a few had undetectable HCV RNA at the end of iv silibinin administration.

It is quite clear that giving an antiviral drug as monotherapy for just 21days is not able to eradicate HCV. The so far shortest successful treatment in HCV genotype 1 patients having the IL28B CC genotype using peginterferon/ribavirin and telaprevir was 12weeks [12]. Comparison with other published reports of iv silibinin (Table 1) shows that the best results in terms of SVR were obtained in patients in whom a low viral load was achieved by administering the drug before transplant and then continuing it for 3–4weeks after transplant [4]. Taken together, the data published so far seem to indicate that HCV RNA levels below the level of quantification (LOQ) at the end of iv silibinin administration and SVR can be reached in 12/14 (85.7%) and 3/14 (21.4%) patients with a continuous pre-/post-transplant administration, respectively, while in patients receiving iv silibinin only after transplant, the same results could be achieved only in 6/35 (17.1%) and 2/35 (5.7%) patients, respectively (Table 1).

Table 1. Cases treated with intravenous silibinin in the transplant setting.

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Studies in the transplant setting are difficult to design. The problems even increase if patients immediately prior to transplantation are involved. They are usually very sick and safety becomes the prime issue. Pretreating patients with iv-SIL is feasible and safe, but is limited by the need of daily infusions. The optimal timing for transplantation would be if the patient becomes HCV RNA undetectable, but the timing of transplantation depends on the availability of a donor organ, which is increasingly challenging in an era of donor organ shortage. Therefore, in some patients, infusion therapy had to be stopped before transplantation was performed.

In the Barcelona study, this was the case in 4 patients. Iv silibinin was restarted 7 to 38days after the 21days of silibinin administration. HCV below the level of quantification (LOQ) was achieved only in 1 of 4 of them in contrast to all of the 4 patients treated continuously. Similarly, in 3 patients treated pretransplant in our center, no liver was available when the targeted low or undetectable viral load was reached (updated from [13]). One patient even subsequently achieved SVR but died on the waiting list. Obviously the best approach would be to do the study at centers offering living donor transplantation. In such centers, treatment and transplantation can be scheduled exactly. A very important aspect in such a study would be to investigate the needed duration of silibinin monotherapy and/or the need for consecutive treatment with peginterferon/ribavirin, possibly in combination with a direct acting antiviral agent. It is conceivable that the optimization of the duration of treatment with iv-SIL, even after cadaveric donor transplantation (e.g., for at least 4weeks) and/or combination therapy could improve the virological response by reducing viral load in the first weeks after transplantation. This may prevent, delay, or decrease the severity of recurrent hepatitis C, with favourable histological findings at 6–12months [14]. This would represent per se a clinically relevant outcome.

So what do we learn from these studies? Iv-SIL is safe but by the currently used applications cannot prevent graft reinfection or eradicate HCV from the transplanted liver in most patients. At present there is no alternative of an interferon-free approach in the peritransplant setting and silibinin may be the ideal drug until safe and effective HCV RNA polymerase inhibitors with a high genetic barrier become available. Nevertheless, there is a need for improvements in treatment schedules before such a treatment can be recommended. Flushing the liver graft with a solution containing silibinin as it has been done to prevent oxidative damage to the liver [15] should be tested in order to determine if it helps prevent recurrence.

Conflict of interest
PF is a member of the global advisory boards of Roche, MSD, Vertex/Tibotec, Madaus–Rottapharm, Böhringer Ingelheim, Idenix, Gilead and Achillion.
He receives an unrestricted research grant from Roche Austria and MSD Austria.

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